Project Summary Despite suppression of the Human Immunodeficiency Virus (HIV) in the periphery, HIV-infected monocytes readily traffic the virus to the central nervous system (CNS). Up-regulation of peripheral mononuclear cells expressing pro-inflammatory cytokines leads to neurotoxic effects of the virus throughout the CNS, including structures that support cardio-autonomic regulation. This migration and infiltration of pro-inflammatory immune cells is also key in the pathogenesis of inflammatory endothelial vascular disease. Catecholamine signaling plays a major role in this vicious cycle of cerebrovascular and endothelial dysfunction. Tonic elevation of plasma catecholamines and pro-inflammatory cytokine levels are linked to reduced colony-forming capacity of endothelial progenitor cells. Although sympathetic-parasympathetic imbalance has been reported in patients since the beginning of the HIV epidemic and prevalence of cardio-metabolic disease comorbidity continues to rise there has been no formal investigation into the central control of autonomic nervous system dysfunction in HIV. This study proposes the use of functional neuroimaging to determine whether HIV and/or pre- hypertension (pre-HTN) has an additive or interactive effect on cardiovascular (CV) reactivity via an altered brain activity and connectivity within structures that control heart rate and blood pressure. The study aims to examine these mechanisms at rest, during mental stress, and following anger rumination. A second goal of this study is to determine whether a change in respiratory rate during these states may provide a cardioprotective effect. The candidate will assess functional brain activity through fMRI scans while simultaneously gathering data on heart rate, continuous blood pressure, and respiratory rate. The candidate will also collect blood in order to assess estrogen levels, and to isolate and enumerate endothelial progenitor cells (EPCs) and inflammatory monocytes. The candidate will also learn the techniques to measure vascular endothelial function through flow- mediated dilation of the brachial artery. Data will be collected from a total of 72 men and 72 women, aged from 35 to 65 years, during Years 1-4 of the grant. The total sample of 144 adults will be divided equally into 4 groups (36 HIV+ pre-HTN, 36 HIV+ NTN, 36 HIV- pre-HTN, and 36 HIV- NTN. This will allow the candidate to determine whether HIV or HTN disease processes are linked to CV regulation while controlling for biologically relevant variables such as cellular and vascular endothelial function and presence of sex hormones. The secondary aim of this study is to assess the plasticity of this central-autonomic network by determining whether manipulation of breathing rate can alter blood pressure and heart rate reactivity during the afore- mentioned behavioral manipulations. Specifically, the plasticity of the baroreflex and brain networks supporting the coordination of heart rate, blood pressure, and respiration will be evaluated within the context of HIV and pre-HTN disease state. Data from this project will inform an R01 study focused on implementing a paced breathing intervention to reduce the risk of HTN in persons living with HIV.